Given the vast amount of information about photoreceptor structure and function, and the underlying biochemistry, the field is poised for significant advances in the understanding of vertebrate (and, ultimately, human) phototransduction, permitting a tight linkage between macroscopic photoreceptor behavior and underlying molecular mechanisms. Such integration will contribute significantly to a full understanding of the essential input elements of the visual system, the photoreceptors. The overall goal of this proposal is the development of an integrated, biochemically-motivated model of vertebrate phototransduction that provides a comprehensive account of the critical features of vertebrate rod responses under both dark-adapted and light-adapted conditions. The research will focus on key unresolved issues in transduction, which may be grouped into those relating to photoreceptor activation and deactivation over their full dynamic range, and those relating to responses over a full range of light-adapted conditions. To ensure maximal accuracy and physiological relevance, models will be constrained by current estimates of relevant biochemical pathways and parameters within the biochemical cascade, and will be quantitatively optimized to fit responses of individual photoreceptors. The quality of the models will be evaluated for goodness of fit to the physiological data, and will be compared with alternative models. A complete account of activation, recovery and light-adapted responses would fully account for both temporal properties and sensitivity of photoreceptors. These properties completely characterize the photoreceptor signal available to the rest of the visual system. Thus, clarification of the phototransduction issues have direct relevance to understanding the role photoreceptors play in shaping the temporal properties and sensitivity of human vision. Successful development of a comprehensive, biochemically-based model can provide powerful tools for evaluating new candidate mechanisms for phototransduction. Similarly, such models allow one to test, noninvasively, putative mechanisms that may be associated with retinal diseases associated with photoreceptor function, and to identify receptoral immaturities in developing visual systems.